AKAP8

Summary

AKAP8 (A-kinase anchoring protein 8, HGNC:378) is a protein-coding gene on chromosome 19p13.12, encoding A-kinase anchor protein 8 (O43823). Anchoring protein that mediates the subcellular compartmentation of cAMP-dependent protein kinase (PKA type II).

This gene encodes a member of the A-kinase anchor protein family. A-kinase anchor proteins are scaffold proteins that contain a binding domain for the RI/RII subunit of protein kinase A (PKA) and recruit PKA and other signaling molecules to specific subcellular locations. This gene encodes a nuclear A-kinase anchor protein that binds to the RII alpha subunit of PKA and may play a role in chromosome condensation during mitosis by targeting PKA and the condensin complex to chromatin. A pseudogene of this gene is located on the short arm of chromosome 9.

Source: NCBI Gene 10270 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 198 total — 1 pathogenic
• MANE Select transcript: NM_005858

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:378
Approved symbol	AKAP8
Name	A-kinase anchoring protein 8
Location	19p13.12
Locus type	gene with protein product
Status	Approved
Aliases	AKAP95, DKFZp586B1222
Ensembl gene	ENSG00000105127
Ensembl biotype	protein_coding
OMIM	604692
Entrez	10270

Gene structure

Transcript identifiers

Ensembl transcripts: 17 — 7 protein_coding, 4 retained_intron, 4 nonsense_mediated_decay, 2 protein_coding_CDS_not_defined

ENST00000269701, ENST00000537303, ENST00000595416, ENST00000598597, ENST00000599883, ENST00000679798, ENST00000680199, ENST00000680245, ENST00000680336, ENST00000680461, ENST00000681018, ENST00000681812, ENST00000931390, ENST00000931391, ENST00000955071, ENST00000955072, ENST00000955073

RefSeq mRNA: 1 — MANE Select: NM_005858 NM_005858

CCDS: CCDS12329

Canonical transcript exons

ENST00000269701 — 14 exons

Exon	Start	End
ENSE00001273547	15379713	15379787
ENSE00003091124	15353385	15355370
ENSE00003464259	15362110	15362251
ENSE00003473891	15360848	15360978
ENSE00003517606	15368235	15368322
ENSE00003534508	15374603	15374635
ENSE00003565123	15358967	15359062
ENSE00003590354	15361729	15361822
ENSE00003600967	15373786	15374065
ENSE00003622455	15372218	15372347
ENSE00003669777	15370146	15370179
ENSE00003678657	15371952	15371998
ENSE00003690695	15372851	15373340
ENSE00003692201	15376976	15377014

Expression profiles

Bgee: expression breadth ubiquitous, 283 present calls, max score 96.77.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 23.3319 / max 165.0067, expressed in 1816 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
179735	16.8469	1805
179736	4.9899	1670
179737	1.4951	994

Top tissues by expression

288 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
sural nerve	UBERON:0015488	96.77	gold quality
granulocyte	CL:0000094	90.80	gold quality
right uterine tube	UBERON:0001302	90.44	gold quality
calcaneal tendon	UBERON:0003701	90.00	gold quality
gastrocnemius	UBERON:0001388	89.69	gold quality
mucosa of stomach	UBERON:0001199	89.58	gold quality
muscle of leg	UBERON:0001383	89.27	gold quality
small intestine Peyer’s patch	UBERON:0003454	89.23	gold quality
metanephros cortex	UBERON:0010533	89.14	gold quality
left uterine tube	UBERON:0001303	89.13	gold quality
spleen	UBERON:0002106	88.94	gold quality
body of uterus	UBERON:0009853	88.80	gold quality
skin of leg	UBERON:0001511	88.79	gold quality
left ovary	UBERON:0002119	88.48	gold quality
transverse colon	UBERON:0001157	88.47	gold quality
right ovary	UBERON:0002118	88.40	gold quality
subcutaneous adipose tissue	UBERON:0002190	88.39	gold quality
skin of abdomen	UBERON:0001416	88.32	gold quality
endocervix	UBERON:0000458	88.30	gold quality
tendon	UBERON:0000043	88.20	gold quality
muscle layer of sigmoid colon	UBERON:0035805	88.20	gold quality
tibial artery	UBERON:0007610	88.13	gold quality
body of stomach	UBERON:0001161	88.12	gold quality
popliteal artery	UBERON:0002250	88.10	gold quality
apex of heart	UBERON:0002098	88.07	gold quality
small intestine	UBERON:0002108	88.07	gold quality
right adrenal gland	UBERON:0001233	87.95	gold quality
tibial nerve	UBERON:0001323	87.95	gold quality
right adrenal gland cortex	UBERON:0035827	87.89	gold quality
right lobe of thyroid gland	UBERON:0001119	87.86	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.78
E-CURD-10	no	243.47
E-ENAD-17	no	166.25
E-MTAB-8060	no	153.21

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

76 targeting AKAP8, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-520G-5P	99.99	66.76	658
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502
HSA-MIR-548AK	99.94	71.24	3488
HSA-MIR-548AM-5P	99.94	71.24	3488
HSA-MIR-548AP-5P	99.94	71.14	3489
HSA-MIR-548AQ-5P	99.94	71.34	3426
HSA-MIR-548AR-5P	99.94	71.28	3515
HSA-MIR-548AS-5P	99.94	71.22	3482
HSA-MIR-548AU-5P	99.94	71.24	3488
HSA-MIR-548AY-5P	99.94	71.23	3502
HSA-MIR-548B-5P	99.94	71.23	3502
HSA-MIR-548BB-5P	99.94	71.27	3509
HSA-MIR-548C-5P	99.94	71.24	3488
HSA-MIR-548D-5P	99.94	71.23	3502
HSA-MIR-548H-5P	99.94	71.24	3488
HSA-MIR-548I	99.94	71.25	3481
HSA-MIR-548J-5P	99.94	71.14	3489
HSA-MIR-548O-5P	99.94	71.24	3488
HSA-MIR-548W	99.94	71.24	3488

Literature-anchored findings (GeneRIF, showing 18)

• AMY-1 interacts with S-AKAP84 and this protein in the cytoplasm and the nucleus, respectively, and inhibits cAMP-dependent protein kinase activity by preventing binding of its catalytic subunit to A-kinase-anchoring protein (AKAP) complex. (PMID:12414807)
• role of AKAP95 in DNA replication by providing a scaffold for MCM2 (PMID:12740381)
• AKAP95 is a potential carrier protein for active caspase 3 from the cytoplasm into the nuclei in apoptotic cells. (PMID:16227597)
• Ectopic AKAP95 stimulates expression of a chromosomal reporter gene in synergy with MLL1 or MLL2, whereas AKAP95 depletion impairs retinoic acid-mediated gene induction in embryonic stem cells (PMID:23995757)
• These results suggest that AKAP8 is involved in the regulation of chromatin structural changes through nuclear tyrosine phosphorylation. (PMID:25770215)
• Gene dosage at 19p13.12, and AKAP8 and/or AKAP8L in particular, play an important role in modulation of head size and may contribute to autism risk. (PMID:26076356)
• The data indicate that AKAP95 is a novel nucleolus-associated protein with a regulatory role on rRNA production. (PMID:26683827)
• Report expression of connexin 43 in ovarian cancer cells in G1/S phase. (PMID:26823747)
• These results establish AKAP95 as a mostly positive regulator of pre-mRNA splicing and a possible integrator of transcription and splicing regulation. (PMID:27824034)
• Using a BioID proximity-based proteomic screen, we identify the nuclear pore complex protein TPR as a novel AKAP95 binding partner. We show interaction between AKAP95 and TPR in mitosis, and an AKAP95-dependent enrichment of TPR in the spindle microtubule area in metaphase, then later in the spindle midzone area. (PMID:28379780)
• Results suggest that ALK generated by alternative transcription Initiation induces chromatin structural changes and heterochromatinization through phosphorylation of AKAP8 in the nucleus. (PMID:29093346)
• The PKA-binding domain of AKAP8 and the C-terminal domain of DPY30, also called Dpy-30 motif, are crucial for the interaction between these proteins. AKAP8 interacts with DPY30 and the RII alpha regulatory subunit of PKA both in the interphase and in mitotic cells. A single amino acid substitution in DPY30 L69D affects its dimerization and completely abolishes its interaction with AKAP8. (PMID:29288530)
• The results of the present study demonstrate a crucial role for AKAP95 in CYP19A1 expression and oestrogen synthesis in humans luteinized granulosa cells, which implies that AKAP95 may be involved in the pathogenesis of polycystic ovary syndrome. (PMID:29397057)
• It consists of AKAP95, PKA, and PDE4D5 and show that it forms a functional cyclic AMP (cAMP) signaling microdomain. (PMID:30982750)
• Identification of A-Kinase Anchor Protein (AKAP8) as a splicing regulatory factor that impedes EMT and breast cancer metastasis. AKAP8 not only is capable of inhibiting splicing activity of the EMT-promoting splicing regulator hnRNPM through protein-protein interaction, it also directly binds to RNA and alters splicing outcomes. Genome-wide analysis shows that AKAP8 promotes an epithelial cell state splicing program. (PMID:31980632)
• A-Kinase Anchoring Proteins Diminish TGF-beta1/Cigarette Smoke-Induced Epithelial-To-Mesenchymal Transition. (PMID:32028718)
• Biophysical properties of AKAP95 protein condensates regulate splicing and tumorigenesis. (PMID:32719551)
• A-Kinase Anchor Protein 95 Is Involved in ERK1/2-Elk-1 Signal Transduction in Colon Cancer. (PMID:36691407)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Akap8	ENSMUSG00000024045
rattus_norvegicus	Akap8	ENSRNOG00000006559

Paralogs (2): AKAP8L (ENSG00000011243), ZNF326 (ENSG00000162664)

Protein

Protein identifiers

A-kinase anchor protein 8 — O43823 (reviewed: O43823)

Alternative names: A-kinase anchor protein 95 kDa

All UniProt accessions (5): A0A7P0T893, A0A7P0TAA4, A0A7P0TBC8, M0QX51, O43823

UniProt curated annotations — full annotation on UniProt →

Function. Anchoring protein that mediates the subcellular compartmentation of cAMP-dependent protein kinase (PKA type II). Acts as an anchor for a PKA-signaling complex onto mitotic chromosomes, which is required for maintenance of chromosomes in a condensed form throughout mitosis. Recruits condensin complex subunit NCAPD2 to chromosomes required for chromatin condensation; the function appears to be independent from PKA-anchoring. May help to deliver cyclin D/E to CDK4 to facilitate cell cycle progression. Required for cell cycle G2/M transition and histone deacetylation during mitosis. In mitotic cells recruits HDAC3 to the vicinity of chromatin leading to deacetylation and subsequent phosphorylation at ‘Ser-10’ of histone H3; in this function may act redundantly with AKAP8L. Involved in nuclear retention of RPS6KA1 upon ERK activation thus inducing cell proliferation. May be involved in regulation of DNA replication by acting as scaffold for MCM2. Enhances HMT activity of the KMT2 family MLL4/WBP7 complex and is involved in transcriptional regulation. In a teratocarcinoma cell line is involved in retinoic acid-mediated induction of developmental genes implicating H3 ‘Lys-4’ methylation. May be involved in recruitment of active CASP3 to the nucleus in apoptotic cells. May act as a carrier protein of GJA1 for its transport to the nucleus. May play a repressive role in the regulation of rDNA transcription. Preferentially binds GC-rich DNA in vitro. In cells, associates with ribosomal RNA (rRNA) chromatin, preferentially with rRNA promoter and transcribed regions. Involved in modulation of Toll-like receptor signaling. Required for the cAMP-dependent suppression of TNF in early stages of LPS-induced macrophage activation; the function probably implicates targeting of PKA to NFKB1.

Subunit / interactions. Binds to the PKA RII-alpha regulatory subunit PRKAR2A (phosphorylated at ‘Thr-54’) during mitosis. Interacts (via C-terminus) with FIGN. Interacts with NCAPD2, CCND1, MCM2, RPS6KA1, PDE4A. Interacts with CCND3, CCNE1, DDX5, CASP3. Interacts with NFKB1; detetcted in the cytoplasm. Interacts with MYCBP; MYCBP is translocated to the nucleus and the interaction prevents the association of the PKA catalytic subunit leading to suppression of PKA activity. Interacts with DPY30; mediating AKAP8 association with at least the MLL4/WBP7 HMT complex. Interacts with HDAC3; increased during mitosis. Interacts with GJA1; in the nucleus and in the nuclear membrane; the nuclear association increases with progress of cell cycle G1, S and G2 phase and decreases in M phase.

Subcellular location. Nucleus. Nucleus matrix. Nucleolus. Cytoplasm.

Tissue specificity. Highly expressed in heart, liver, skeletal muscle, kidney and pancreas. Expressed in mature dendritic cells.

Post-translational modifications. Phosphorylated on tyrosine residues probably by SRC subfamily protein kinases; multiple phosphorylation is leading to dissociation from nuclear structures implicated in chromatin structural changes.

Similarity. Belongs to the AKAP95 family.

RefSeq proteins (1): NP_005849* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR007071	AKAP95	Family
IPR034736	ZF_C2H2_AKAP95	Domain

Pfam: PF04988

UniProt features (45 total): region of interest 12, modified residue 11, compositionally biased region 8, mutagenesis site 7, zinc finger region 2, cross-link 2, chain 1, short sequence motif 1, sequence variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O43823-F1	53.67	0.03

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (13): 109, 109, 112, 199, 233, 277, 323, 328, 339, 662, 685, 317, 567

Mutagenesis-validated functional residues (7):

Position	Phenotype
290	no nuclear localization; when associated with 304-n-s-305.
304–305	no nuclear localization; when associated with s-290.
392	abolishes chromosome-condensation activity; when associated with s-395.
395	abolishes chromosome-condensation activity; when associated with s-392.
481	abolishes chromosome-condensation activity and recruitment of condensin complex; when associated with s-484.
484	abolishes chromosome-condensation activity and recruitment of condensin complex; when associated with s-481.
582	no effect on activity to regulate dna replication and on condensin complex recruitment.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 187 (showing top): GOBP_CHROMOSOME_ORGANIZATION, GOBP_RESPONSE_TO_PROSTAGLANDIN_E, GOBP_CELLULAR_RESPONSE_TO_LIPID, GOBP_CELLULAR_RESPONSE_TO_BIOTIC_STIMULUS, GOBP_CELLULAR_RESPONSE_TO_PROSTAGLANDIN_STIMULUS, GOBP_CELL_CYCLE_PHASE_TRANSITION, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN, GOBP_CELLULAR_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, GOBP_CHROMOSOME_CONDENSATION, GOBP_NEGATIVE_REGULATION_OF_MULTICELLULAR_ORGANISMAL_PROCESS, GOBP_DEFENSE_RESPONSE_TO_OTHER_ORGANISM, GOBP_ORGANELLE_FISSION, GOBP_CELLULAR_RESPONSE_TO_HORMONE_STIMULUS, GOBP_RESPONSE_TO_PROSTAGLANDIN

GO Biological Process (10): mitotic cell cycle (GO:0000278), mitotic chromosome condensation (GO:0007076), signal transduction (GO:0007165), protein transport (GO:0015031), negative regulation of tumor necrosis factor production (GO:0032720), cell cycle G2/M phase transition (GO:0044839), innate immune response (GO:0045087), cellular response to lipopolysaccharide (GO:0071222), cellular response to prostaglandin E stimulus (GO:0071380), immune system process (GO:0002376)

GO Molecular Function (9): double-stranded DNA binding (GO:0003690), RNA binding (GO:0003723), zinc ion binding (GO:0008270), protein kinase A regulatory subunit binding (GO:0034237), histone deacetylase binding (GO:0042826), NF-kappaB binding (GO:0051059), DNA binding (GO:0003677), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (8): condensed chromosome (GO:0000793), female pronucleus (GO:0001939), nucleus (GO:0005634), nucleoplasm (GO:0005654), nucleolus (GO:0005730), cytoplasm (GO:0005737), membrane (GO:0016020), nuclear matrix (GO:0016363)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
nuclear lumen	3
nucleic acid binding	2
cell cycle	1
mitotic nuclear division	1
mitotic sister chromatid segregation	1
mitotic cell cycle	1
chromosome condensation	1
mitotic cell cycle process	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
transport	1
intracellular protein localization	1
establishment of protein localization	1
tumor necrosis factor production	1
regulation of tumor necrosis factor production	1
negative regulation of tumor necrosis factor superfamily cytokine production	1
cell cycle phase transition	1
immune response	1
defense response to symbiont	1
response to lipopolysaccharide	1
cellular response to molecule of bacterial origin	1
cellular response to lipid	1
cellular response to oxygen-containing compound	1
response to prostaglandin E	1
cellular response to prostaglandin stimulus	1
cellular response to alcohol	1
cellular response to ketone	1
biological_process	1
DNA binding	1
transition metal ion binding	1
protein kinase A binding	1
enzyme binding	1
RNA polymerase II-specific DNA-binding transcription factor binding	1
binding	1
cation binding	1
chromosome	1

Protein interactions and networks

STRING

1072 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
AKAP8	AKAP1	Q92667	900
AKAP8	AKAP5	P24588	842
AKAP8	PRKACA	P17612	804
AKAP8	PRKACG	P22612	803
AKAP8	PRKACB	P22694	803
AKAP8	DPY30	Q9C005	765
AKAP8	AKAP10	O43572	707
AKAP8	AKAP11	Q9UKA4	698
AKAP8	AKAP9	Q99996	696
AKAP8	CBFA2T2	O43439	669
AKAP8	AKAP13	Q12802	630
AKAP8	DHX9	Q08211	627
AKAP8	PDE4A	P27815	623
AKAP8	AKAP7	O43687	592
AKAP8	CBFA2T3	O75081	578

IntAct

175 interactions, top by confidence:

A	B	Type	Score
YWHAB	PIK3C2A	psi-mi:“MI:0914”(association)	0.800
HDAC3	AKAP8	psi-mi:“MI:0914”(association)	0.650
AKAP8	HDAC3	psi-mi:“MI:0914”(association)	0.650
HDAC3	AKAP8	psi-mi:“MI:0915”(physical association)	0.650
AKAP8	HDAC3	psi-mi:“MI:0403”(colocalization)	0.650
HDAC3	AKAP8	psi-mi:“MI:0403”(colocalization)	0.650
YWHAG	BLTP3B	psi-mi:“MI:0914”(association)	0.640
DPY30	AKAP8	psi-mi:“MI:0914”(association)	0.610
DPY30	AKAP8	psi-mi:“MI:0915”(physical association)	0.610
AKAP8	MCM2	psi-mi:“MI:0915”(physical association)	0.580
MCM2	AKAP8	psi-mi:“MI:0915”(physical association)	0.580
AKAP8	WDR5	psi-mi:“MI:0915”(physical association)	0.580
AKAP8	ASH2L	psi-mi:“MI:0915”(physical association)	0.580
AKAP8	WDR5	psi-mi:“MI:0914”(association)	0.580
AKAP8	PRKAR2A	psi-mi:“MI:0407”(direct interaction)	0.570

BioGRID (246): AKAP8 (Affinity Capture-RNA), AKAP8 (Affinity Capture-MS), AKAP8 (Affinity Capture-MS), AKAP8 (Affinity Capture-MS), AKAP8 (Affinity Capture-MS), AKAP8 (Affinity Capture-MS), AKAP8 (Affinity Capture-MS), AKAP8 (Affinity Capture-MS), AKAP8 (Affinity Capture-MS), AKAP8 (Co-fractionation), EEF1B2 (Co-fractionation), RUVBL1 (Co-fractionation), RUVBL2 (Co-fractionation), TUBB4B (Co-fractionation), AKAP8 (Proximity Label-MS)

ESM2 similar proteins: A0A140LFM6, A2CEZ5, A2RV70, A2VCZ5, A5WUN7, A6H5Y1, A8MW92, B0S6S9, D3ZJ47, E7FAP1, O43823, O70343, P62932, Q16533, Q2T9I9, Q499E5, Q4R815, Q5CZC0, Q5REF4, Q5SW75, Q5SWW4, Q5T5Y3, Q63014, Q65Z40, Q66H35, Q6IRN6, Q6JPI3, Q6KAQ7, Q6PCB5, Q71F56, Q76I76, Q76I79, Q865B6, Q865B7, Q8CB14, Q8CDG5, Q8IUR6, Q8IX21, Q8JZS6, Q8K3V7

Diamond homologs: A2CEZ5, A2RV70, F1MJM0, O43823, O88291, Q28F29, Q5BKZ1, Q5RCA4, Q5VK71, Q5ZJ02, Q63014, Q9DBR0, Q9R0L7, Q9ULX6

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
AKAP8	“up-regulates activity”	PRKACA	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 147 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex	6	38.4×	1e-06
Activation of BAD and translocation to mitochondria	5	36.2×	1e-05
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	5	32.0×	2e-05
Activation of BH3-only proteins	6	28.4×	8e-06
Intrinsic Pathway for Apoptosis	7	19.5×	8e-06
RHO GTPases activate PKNs	6	18.1×	4e-05
SARS-CoV-1-host interactions	8	13.4×	1e-05
G1/S Transition	6	13.3×	2e-04

GO biological processes:

GO term	Partners	Fold	FDR
mRNA stabilization	7	19.4×	4e-05
negative regulation of translation	7	10.4×	1e-03
mRNA splicing, via spliceosome	11	7.6×	8e-05
intracellular protein localization	8	6.3×	7e-03
transcription by RNA polymerase II	10	5.3×	4e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

198 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	140
Likely benign	23
Benign	14

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
2499635	GRCh38/hg38 19p13.12-13.11(chr19:15014099-16261691)	Pathogenic

SpliceAI

2199 predictions. Top by Δscore:

Variant	Effect	Δscore
19:15355369:CC:C	acceptor_gain	1.0000
19:15355370:CC:C	acceptor_gain	1.0000
19:15360843:CTCA:C	donor_loss	1.0000
19:15360844:TCAC:T	donor_loss	1.0000
19:15360845:CA:C	donor_loss	1.0000
19:15360846:A:AC	donor_gain	1.0000
19:15360846:AC:A	donor_gain	1.0000
19:15360847:C:CA	donor_loss	1.0000
19:15360847:C:CC	donor_gain	1.0000
19:15360847:CC:C	donor_gain	1.0000
19:15360847:CCCT:C	donor_gain	1.0000
19:15360847:CCCTG:C	donor_gain	1.0000
19:15362105:TTTA:T	donor_loss	1.0000
19:15362108:AC:A	donor_loss	1.0000
19:15362109:C:CT	donor_loss	1.0000
19:15362249:ATT:A	acceptor_gain	1.0000
19:15362250:TT:T	acceptor_gain	1.0000
19:15362252:C:CA	acceptor_loss	1.0000
19:15362252:C:CC	acceptor_gain	1.0000
19:15371950:A:AC	donor_gain	1.0000
19:15371950:ACAC:A	donor_gain	1.0000
19:15371950:ACACC:A	donor_gain	1.0000
19:15371951:C:CC	donor_gain	1.0000
19:15371951:CA:C	donor_gain	1.0000
19:15371951:CACC:C	donor_gain	1.0000
19:15371951:CACCC:C	donor_gain	1.0000
19:15371953:C:CA	donor_gain	1.0000
19:15371996:CAT:C	acceptor_gain	1.0000
19:15371999:C:CC	acceptor_gain	1.0000
19:15371999:CTG:C	acceptor_loss	1.0000

AlphaMissense

4592 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:15358983:A:G	L536P	1.000
19:15359010:A:G	L527S	1.000
19:15359013:A:T	V526D	1.000
19:15359022:G:T	A523D	1.000
19:15360863:G:C	H504Q	1.000
19:15360863:G:T	H504Q	1.000
19:15360865:G:C	H504D	1.000
19:15360881:G:C	H498Q	1.000
19:15360881:G:T	H498Q	1.000
19:15360883:G:C	H498D	1.000
19:15360883:G:T	H498N	1.000
19:15360912:A:T	I488N	1.000
19:15360923:G:C	C484W	1.000
19:15360924:C:A	C484F	1.000
19:15360924:C:G	C484S	1.000
19:15360924:C:T	C484Y	1.000
19:15360925:A:G	C484R	1.000
19:15360925:A:T	C484S	1.000
19:15360927:G:T	A483D	1.000
19:15360932:G:C	C481W	1.000
19:15360933:C:A	C481F	1.000
19:15360933:C:G	C481S	1.000
19:15360933:C:T	C481Y	1.000
19:15360934:A:G	C481R	1.000
19:15360934:A:T	C481S	1.000
19:15360939:G:T	A479D	1.000
19:15361805:T:A	R440S	1.000
19:15361805:T:G	R440S	1.000
19:15361806:C:A	R440I	1.000
19:15361819:A:G	Y436H	1.000

dbSNP variants (sampled 300 via entrez): RS1000143922 (19:15355948 C>A), RS1000203417 (19:15353848 C>A,T), RS1000207351 (19:15380443 G>T), RS1000216337 (19:15374272 C>G,T), RS1000411548 (19:15378953 A>C,G), RS1000464943 (19:15371268 C>T), RS1000539826 (19:15370443 C>T), RS1000540805 (19:15375317 A>C), RS1000594850 (19:15356895 C>A,T), RS1000829008 (19:15361955 C>G,T), RS1000845607 (19:15359476 T>C), RS1000868759 (19:15378702 A>G), RS1000996615 (19:15365898 C>T), RS1001048793 (19:15365702 G>A,C), RS1001103718 (19:15370831 C>T)

Disease associations

OMIM: gene MIM:604692 | disease phenotypes: MIM:613638

GenCC curated gene-disease

Mondo (2): long QT syndrome (MONDO:0002442), chromosome 19p13.13 deletion syndrome (MONDO:0013336)

Orphanet (2): 19p13.13 microdeletion syndrome (Orphanet:357001), 19p13.3 microduplication syndrome (Orphanet:447980)

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

0 associations (top):

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D008133	Long QT Syndrome	C14.280.067.565; C14.280.123.625; C16.131.240.400.715; C23.550.073.547

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

33 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
trichostatin A	decreases expression	2
Valproic Acid	decreases expression, affects expression	2
FR900359	increases phosphorylation	1
TAK-243	decreases sumoylation	1
bisphenol A	decreases methylation	1
sodium arsenate	decreases expression	1
mono-(2-ethylhexyl)phthalate	decreases methylation, increases abundance	1
coumarin	increases phosphorylation	1
di-n-butylphosphoric acid	affects expression	1
azoxystrobin	decreases expression	1
apicidin	decreases expression	1
corosolic acid	increases expression	1
2-palmitoylglycerol	increases expression	1
picoxystrobin	decreases expression	1
3-(2-hydroxy-4-(2-methylnonan-2-yl)phenyl)cyclohexan-1-ol	decreases expression	1
Resveratrol	affects cotreatment, increases expression	1
Temozolomide	increases expression	1
Vorinostat	decreases expression	1
Air Pollutants, Occupational	affects expression	1
Arsenic	affects methylation	1
Camptothecin	increases expression	1
Diethylhexyl Phthalate	decreases methylation, increases abundance	1
Doxorubicin	decreases expression	1
Enzyme Inhibitors	decreases activity, increases O-linked glycosylation	1
Plant Extracts	affects cotreatment, increases expression	1
Progesterone	decreases expression	1
Ribonucleotides	affects binding	1
Rotenone	decreases expression	1
Silicon Dioxide	increases expression	1
Smoke	decreases expression	1

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_XL16	HAP1 AKAP8 (-)	Cancer cell line	Male

Clinical trials (associated diseases)

66 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT02513940	PHASE4	COMPLETED	Influence of Testosterone Administration on Drug-Induced QT Interval Prolongation and Torsades de Pointes
NCT03834883	PHASE4	COMPLETED	Reducing the Risk of Drug-Induced QT Interval Lengthening in Women
NCT04169100	PHASE4	UNKNOWN	Novel Form of Acquired Long QT Syndrome
NCT04675788	PHASE4	COMPLETED	Novel Approaches for Minimizing Drug-Induced QT Interval Lengthening
NCT01648205	PHASE2	COMPLETED	Long-term Efficacy Study of Sodium Channel Blocker in LQT3 Patients
NCT02412709	PHASE2	UNKNOWN	Long QT Syndrome Screening in Newborns
NCT04581408	PHASE2	COMPLETED	Mutation-specific Therapy for the Long QT Syndrome
NCT00316459	PHASE1	COMPLETED	Study Evaluating the Effects of Multiple Oral Doses of ERB-041 on Cardiac Repolarization in Healthy Subjects
NCT01849003	PHASE1	COMPLETED	Study of the Effect of GS-6615 in Subjects With LQT-3
NCT02365532	PHASE1	COMPLETED	Effect of Oral GS-6615 on Dofetilide-Induced QT Prolongation, Safety, and Tolerability in Healthy Adults
NCT02412098	PHASE1	COMPLETED	Pharmacokinetics of Eleclazine in Adults With Normal and Impaired Hepatic Function
NCT02441829	PHASE1	COMPLETED	Pharmacokinetics of Eleclazine in Adults With Normal and Impaired Renal Function
NCT05759962	PHASE1	COMPLETED	Phase 1 Study of LQT-1213 in Healthy Adults
NCT05906732	PHASE1/PHASE2	TERMINATED	Study of LQT-1213 on QTc-induced Prolongation in Healthy Adult Subjects (Part1) and on Congenital Long QT in Patients Diagnosed With Type 2 or 3 Long QT Syndrome (Part 2).
NCT00005176	Not specified	COMPLETED	Long QT Syndrome-Population Genetics and Cardiac Studies
NCT00005250	Not specified	COMPLETED	Linkage Study of Long QT Syndrome In An Amish Kindred
NCT00005367	Not specified	COMPLETED	Epidemiology of Long QTand Asian Sudden Death in Sleep
NCT00221832	Not specified	UNKNOWN	Molecular Genetic Screening and Identification of Congenital Arrhythmogenic Diseases
NCT00292032	Not specified	COMPLETED	Registry of Unexplained Cardiac Arrest
NCT00335036	Not specified	TERMINATED	Pediatric Lead Extractability and Survival Evaluation (PLEASE)
NCT00399412	Not specified	COMPLETED	ECG Signal Collection From Long QT Syndrome, Wide QRS Complexes, Heart Failure, and Cardiac Resynchronization Patients
NCT00488254	Not specified	COMPLETED	The Long QT Syndrome in Pregnancy
NCT00588965	Not specified	COMPLETED	Effect of Beta-blocker Therapy on QTc Response in Exercise and Recovery in Normal Subjects
NCT01705925	Not specified	COMPLETED	Multicenter Evaluation of Children and Young Adults With Genotype Positive Long QT Syndrome
NCT01903564	Not specified	COMPLETED	Fetal and Neonatal Magnetophysiology
NCT02082431	Not specified	COMPLETED	Determine the Incidence of Long QT Amongst a Large Cohort of Subjects Diagnosed With Unilateral or Bilateral Sensorineural Hearing Loss.
NCT02413450	Not specified	ENROLLING_BY_INVITATION	Derivation of Human Induced Pluripotent Stem (iPS) Cells to Heritable Cardiac Arrhythmias
NCT02425189	Not specified	COMPLETED	The Canadian National Long QT Syndrome Registry
NCT02439645	Not specified	TERMINATED	A Registry to Determine the Clinical and Genetic Risk Factors for Torsade De Pointes
NCT02439658	Not specified	UNKNOWN	Genetics of QT Prolongation With Antiarrhythmics
NCT02549664	Not specified	COMPLETED	Exercise in Genetic Cardiovascular Conditions
NCT02581241	Not specified	COMPLETED	Abnormal QT-Response to the Sudden Tachycardia Provoked by Standing in Individuals With Drug-induced Long QT Syndrome
NCT02680080	Not specified	COMPLETED	Effect of Grapefruit on QT Interval in Healthy Volunteers and Patients With Congenital Long QT Syndrome
NCT02775513	Not specified	UNKNOWN	Metabolism of Patients With Genetically Caused Cardiac Arrhythmia
NCT02814981	Not specified	UNKNOWN	Hydroxyzine and Risk of Prolongation of QT Interval
NCT02876380	Not specified	COMPLETED	Prospective Identification of Long QT Syndrome in Fetal Life
NCT03182777	Not specified	COMPLETED	Safety of Local Dental Anesthesia in Patients With Cardiac Channelopathies
NCT03544918	Not specified	COMPLETED	Prevalence of Congenital Long QT Syndrome and Acquired QT Prolongation in a Hospital Cohort
NCT03642405	Not specified	UNKNOWN	Drug-induced Repolarization ECG Changes
NCT03678311	Not specified	COMPLETED	Long QT Syndrome and Sleep Apnea